N&#39;-(4-(hydroxymethyl)-5-pyrazolyl) amidines



United States Patent ice 3,544,585 -[4-(HYDROXYMETHYL) -5-PYRAZOLYL]AMIDINES Leo Ralph Swett and James Daniel Ratajczyk, Waukegan,

and Patrick Richard Young, Winthrop Harbor, 11]., assignors to AbbottLaboratories, North Chicago, 111., a corporation of Illinois No Drawing.Filed Oct. 4, 1967, Ser. No. 672,717

Int. Cl. C07d 49/20 US. Cl. 260-310 2 Claims ABSTRACT OF THE DISCLOSUREA novel series of N'-[4-hydroxymethyl)-5-pyrazolyl] amidines which areuseful as effective anti-inflammatory agents. These compounds areprepared by reacting 5- amino-l,3-disubstituted pyrazole with theappropriate formylated amine, and reducing the product obtained therebyto yield the desired compound.

DESCRIPTION OF INVENTION This invention is directed to a novel series ofchemical compounds having the general structural formula:

I R Y wherein A and W each represent loweralkyl or, A and W togetherform a cyclic secondary amine, in the presence of a suitable catalyst.This reaction yields a pyrazole derivative having the amide condense atthe 5-amino position and the formyl group substituted at the 4-position.This compound is then reduced with any suitable reducing agent to yieldthe final product.

This reaction scheme may be represented as follows:

The reaction is carried out under heat and with an excess of theformylated secondary amine according to the Vilsmeier-Haack aldehydesynthesis reaction. The catalyst generally employed in this reaction isphos- 3,544,585 Patented Dec. 1, 1970 phorous oxychloride since thisagent is unusually suited to accomplish the condensation of the formylgroup at the 4-position of the pyrazole ring. An excess amount offormylated secondary amine must be used since it supplies the formylgroup for the 4-position condensation as Well as supplying material forthe condensation to the amine group at the 5-position on the pyrazolering. That is, the formylated secondary amine supplies the carbon atomadjacent the double bond at the 5-position nitrogen atom.

The formylated secondary amines suitable in the practice of thisinvention include the following: l-formylpiperidine,1-formyl-4-methylpiperazine, diethylformamide, l-formylmorpholine anddimethylformamide. In the case Where R is loweralkyl, other acylatedamines may be used. For example, N,N-dimethylacetamide in the presenceof phosphorous oxychloride condenses with thel,3-disubstituted-S-aminopyrazole to yield N'-(l,3-disubstituted-S-pyrazolyl)-N,N-dimethylacetamidine.

The 4-formyl group can then be introduced into the pyrazole nucleus bythe use of dimethylformamide and phosphorous oxychloride.

In order to better illustrate this invention, reference is made to thefollowing examples which are intended to describe several embodiments ofthe invention, and are not intended to limit same thereby.

EXAMPLE A Preparation of 5-amino-l,3-diphenylpyrazole To a stirredsolution of 550 ml. of water and 150 ml. of concentrated hydrochloricacid, is added dropwise 108 grams (1.0 molar) of phenylhydrazine.Following this addition, 144 grams (1.0 molar) of3-imino-3-phenylpropionitrile is added and the reaction mixture is thenheated to 90 C. for 30 minutes. To the heated reaction mixture is slowlyadded ml. of concentrated hydrochloric acid and the mixture is heated toreflux for one hour. The mixture is then cooled in an ice bath and madealkaline by the addition of about 250 ml. of concentrated ammoniumhydroxide until a precipitate forms.

The precipitate is filtered and Washed thoroughly with Water, thendried. The product is crystallized from ethanol and water yielding 153grams of 5-amino-1,3-diphenylpyrazole having a melting point of 13l-133C.

EXAMPLE B Preparation of S-amino-l-methyl-3-phenylpyrazole A mixture of13 grams (0.09 mole) of benzoylacetonitrile and 4.1 grams (0.09 mole) ofmethylhydrazine is refluxed together in 75 ml. of ethanol for 3 hours.The solvent is then removed in vacuo and the residual oil crystallizedfrom ethyl acetate and a solvent consisting of a mixture of saturatedhydrocarbons consisting mainly of hexane, having a boiling point of 6068C. and commonly known by the trademark Skellysolve B, yielding 8.1 gramsof S-amino-l-methyl-3-phenylpyrazole having a melting point of 124-l26'C.

Although Examples A and B illustrate methods for making theS-amino-l,3-disubstituted pyrazoles necessary as one of the startingmaterials to prepare the compounds of the instant invention, suchmethods are known in the art. Furthermore, the 5-amino-1,3-disubstitutedpyrazoles are known compounds and are therefore not deemed to be a partof this invention, except to the extent that they are starting materialsfor making the novel compounds disclosed herein.

The following examples illustrate methods of preparing various membersof the N'-[4-(hydroxymethy)-5- pyrazolyl]amidine series of thisinvention.

3 EXAMPLE 1 1- [N- [4- (hydroxymethyl) -1 3-diphenyl-5-pyrazolyl]formimidoyl] -piperidine A mixture of 23.5 grams (0.1 mole) of-amino-l,3- diphenylpyrazole and 45 grams (0.4 mole) of formylpiperidineis heated to 70 C. and to this mixture is added dropwise 63 grams (0.41mole) of phosphorous oxychlo ride with stirring. After the addition iscomplete, the mixture is heated to 90 C. for one hour. The mixture isthen poured onto ice and stirred until the complex is hydrolyzed. Asaturated solution of sodium bicarbonate is added until the mixture isalkaline. The crude product is filtered, washed with water andcrystallized from ethanol yielding 12.8 grams of1-[N-(4-formyl-1,3-diphenyl 5 p-yrazolyl) formimidoyl1piperidine, havinga melting point of 140l42. C.

The l[N (4-formyl-1,3-diphenyl-5-pyrazolyl) -formimidoyl]piperidine issuspended in methanol and cooled in an ice bath with stirring. Anequimolar proportion of sodium borohydride is added and the reactionmixture is allowed to come to room temperature and is stirred for 3 to 4hours. A precipitate forms which is filtered off. Water is added to thefiltrate until crystallization begins, and the precipitate is filteredand dried. Recrystallization from ethyl acetate yields 7.4 grams ofl-[N-[4-(hydroxymethyl) 1,3 diphenyl 5-pyrazolyl]formimidoy11piperidine,having a melting point of 170-17l C.

Following the procedure of Example 1, the other members of this seriesof compounds may be similarly prepared. That is, the desired compound isobtained by reacting the appropriate S-amino-1,3-disubstituted pyrazolewith the corresponding formylated secondary amine and phosphorousoxychloride, and reducing the product of this reaction with a suitablereducing agent such as sodium borohydride, lithium aluminum hydride, orother known reducing agents. Table I following below lists severalspecific embodiments prepared in accordance with this procedure. ColumnsA and B describe the reactants, Column C, the product, and Column D, anidentifying physical constant, e.g., melting point in degreescentigrade.

phenyl-S-pyrazolyl]-N,N-dimethylacetamidine, having a melting point of140-142 C.

Following the procedure of Example A and by using the appropriatelysubstituted halophenylhydrazine in place of phenylhydrazine, one mayprepare the S-amino-l-halophenylpyrazoles according to the followingreaction scheme:

@wz-omorr hell-@NHNH:

| hal This material may then be used as starting material in accordancewith the procedure of Example 1 to give the 4-formyl derivative which onreduction yields a halosubstituted phenyl moiety in the l-position ofthe pyrazole ring. Examples of such compounds includeN'[4-(hydroxymethyl) 1-(4-fluorophenyl)-3-phenyl-5pyrazolyl]- N,Ndimethylformamidine; N [4 (hydroxymethyl) 1 (4 chlorophenyl) 3-phenyl 5pyrazolyl] N,N-dimethyl formamidine; N [4 (hydroxymethyl) 1 (4- I TABLEI A B 0* D Example:

2 5-amino1,3-diphenylpyrazole 1-f0nnyl-4-methylpiperazine1-[N-[4-(hydroxymethyl)-1,3-diphenyl5- 126-128pyrazolyl]-formimidoy1]-4-methyl iperazine. 35-amino-1,3-dipheny1pyrazole DiethylformamideN,N-diethy1-N'-[4-(hydroxymethyl -1,3- 152-154diphenyl-5-pyrazolyl]formamidine. 4 Eamino-lfi-diphenylpyramle4-formylm0rpho1ine 4-[N-[4-(hydroxymethyl)-1,3-di henyl-5- 170-172pyrazolyl]l'orm.imidoyl]morpholine. 55-amino-3-methyl-l-phenylpyrazole-... DimethylformamideN-[4-(hydroxymethyD-3-methyl-l-phenyl-s- 118-120pyrazolyl]-N,N-dimethylformamidjne. 65-amino-l-methyl-3-phenylpy'razOle.-.. DimethylformamideN-[4-(hydroxymethyl)-1-methyl-3-pheny1-5- 132-133pyrazolyl]N,N-dimethylformamidine. 7 5amino-1,3-diphenylpyraz0leDimethylformamide N-[4(hydroxymethyl)-1,3-diphenyl-5- 149-151 Vpyrazolyl]-N,N-dimethyliormamidine. 8 5-amino-1,3-dimethylpyraz01eDimethylformamide N -[4-(hydroxymethyl)-1,3-dimethyl-5- 93-000pyrazolyl]-N,N-dimethylformamidine. 9 s-amino-l-phenylpyrazoleDunethylt'onnamide N-[4-(hydroxymethyl)-1- heny1-5-pyrazoly11- OilN,N-dimethylformamidine.

*The compounds shown in this column represent the final productsobtained after reduction of the intermediate formed by the reaction ofthe starting materials listed in Columns A and B.

EXAMPLE 10 N-[4-(hydroxymethyl)-1,3-diphenyl-5-pyrazolyl]N,Ndimethylacetamidine Following the procedure of Example 1, 23.5 grams(0.1 mole) of S-amino-1,3-diphenylpyrazole is reacted with 35 grams (0.4mole) of N,N-dimethylacetamide and phosphorous oxychloride.Crystallization from ethanol yields 16.8 grams ofN-(1,3-diphenyl-5-pyrazolyl)-N,N- dimethylacetamidine. The compound isthen reacted with dimethylformamide and phosphorous oxychloride,repeating the same reaction scheme yielding N'-(4-forn1yl-1,3-diphenyl-5-pyrazolyl)-N,N-dimethylacetamidine. This intermediate isthen reduced by reaction with sodium The compounds of this inventionexhibit valuable pharmacological properties, especially asanti-inflammatory and anti-pyretic agents. In order to illustrateanti-pyretic properties, a group of rats are injected with Brewers yeastby intramuscular injection to produce a feverish condition. The group issplit into a control group and a test group. When the fever hasstabilized at 3 degrees F. or higher, the test compounds areadministered to the test group and placebos to the control group.Administration may be oral or by injection. Rectal temperatures aretaken at hourly intervals after administration. The 3 hour reading isused to calculate fever and percent reduction in fever between drug andplacebo groups.

Table II below shows the results from a representative borohydrideyielding N [4 (hydroxymethyl) 1,3 dinumber of the compounds of theinstant invention. In each case, administration is by the oral route.The doses indicated in the table are given in terms of milligrams perkilogram of body weight of the rat. The term LD represents the dosage atwhich the test compound is toxic to 50 percent of the animals in thetest group.

TABLE II Percent reduction Dose, mgJkg.

Compound mgJkg.

Number:

1 N-[4-(hydroxymethyl)- 1,3-diphenyl-5-pyrazo1y1]-N,N-dimethy1- formamie.

2 N-[4-(hydroxymethyl)- In order to demonstrate anti-inflammatoryactivity, a modification of the method described by C. A. Winter, etal., Proc. Soc. Exp. Med., 1962, 1112544 is utilized. Test compounds areadministered to a group of test rats 30 minutes prior to an injection ofcarrageenan into the hind paw of the rats. Peak edema occurs 3 hoursafter the phlogistic injection, at which time the percent inhibition iscalculated from the difference between the drug and placebo groups. Thecontrol group is administered water or saline as the placebo.Administration may be by the oral route or by injection.

Table HI below shows the results for a representative number of thecompounds of this invention when tested according to this procedure. Ineach case, the compounds are administered by the oral route. The dosagesare given in terms of milligrams of compound per kilogram of animal bodyweight. Again, the LD represents the dosage at which the test compoundis toxic to 50 percent of the morpholine.

The compounds of this invention may be administered orally, or asinjectable solutions. Oral administration includes tablet preparationsas well as oral suspensions and emulsions. Administration by injectionincludes intramuscular, intraperitoneal as well as intravenousinjections. Methods for formulating such preparations as tablets,emulsions, and injecta-ble solutions are generally known in the art.

We claim:

1. A chemical compound having the formula:

I R Y wherein X is selected from the group consisting of phenyl andloweralkyl; Y is selected from the group consisting of phenyl,loweralkyl and halophenyl; R is a member selected from the groupconsisting of hydrogen and loweralkyl; and R is a member selected fromthe group consisting of diloweralkylamino, piperidino, l-piperazinyl,4-methyl-l-piperazinyl, and morpholino.

2. A compound according to claim 1 wherein X and Y are each phenyl, R ishydrogen and R is dimethylamino.

References Cited UNITED STATES PATENTS 2,858,309 10/1958 Druey et al.260-310C 3,318,904 5/1967 Schmidt et al. 260268Het 3,404,143 10/1968Hebky et al. 260-564 OTHER REFERENCES Arndt et al. I German Application1,172,081, June 1964 (2 page spec.), 260-564.

Arndt et al. II German Application 1,220,195, June 1966 (3 page spec.),260-564.

Finar et al. Jour. Chem. Soc. (London), 1959, pp. 1819-23, QD1.C6.

Hill et al. Jour. Amer. Chem. Soc., vol. 48, pp. 3214- 19 (1926),QD1.A5.

Musante et al. 62122. Chim. Ital, vol. 89, p. 1582 relied on (1959),QD1.G28.

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Wagner et al. Synthetic Organic Chemistry, pp. 635-6, N.Y., Wiley, 1953,QD262.W24.

NATALIE TROUSOF, Primary Examiner US. Cl. X.R.

